Summary of work: Novel potent and selective inhibitors of the enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, have been developed for the treatment of a variety of neurological diseases, including Alzheimer's disease and myasthenia gravis. Phenserine and analogues, loosely related to the structure of the natural alkaloid physostigmine, are selective inhibitors of AchE with optimal brain uptake and a long duration of action. Phenserine demonstrates an unusually wide therapeutic window and robustly improves cognitive activity in rodent learning and memory paradigms at doses that are some 60-fold lower than maximum daily tolerated ones. Both rodent and canine studies have demonstrated its favorable toxicological profile when administered in high doses for up to 3 months, and required studies to support FDA approval for its entry into clinical assessment for the treatment of Alzheimer's disease have been completed. Assays to support clinical pharmacokinetics and dynamics have been developed and potential metabolites synthesized and chemically characterized. Novel inhibitors of BchE have been developed to inhibit the synthesis and secretion of beta-APP, the source of the purative Alzheimer neurotoxic peptide beta-amyloid, A beta. Additionally, studies of nicotinic agonists and antagonists administered to rodents have demonstrated the ability of these agents to modulate CSF levels of beta-APP and A beta. On the basis of this, further potent nicotinic agents are being synthesized and assessed. Potential targets for the treatment of AIDS Dementia Complex (ADC), a late stage neuropathological condition manifested by defective cognitive and motor functions in the majority of afflicted individuals, are being characterized for later drug development. Research is on going to elucidate the etiology of HIV entry into the brain, examine the effects of HIV glycoproteins in modulating normal blood-brain barrier function; and investigate possible common neuropathological pathways between ADC and other dementias.